Sepsis Management in 2025

 

Contemporary Approaches to Sepsis Management in 2025: A Critical Care Perspective

Dr Neeraj Manikath ,claude.ai

Abstract

Background: Sepsis remains a leading cause of morbidity and mortality in critically ill patients, with an estimated global burden of 48.9 million cases annually. Recent advances in understanding sepsis pathophysiology, biomarker identification, and therapeutic interventions have transformed management paradigms.

Objective: To provide critical care practitioners with an evidence-based update on sepsis recognition, risk stratification, and management strategies incorporating the latest clinical guidelines and emerging therapies.

Methods: Comprehensive review of current literature, international guidelines, and recent clinical trials through January 2025.

Conclusions: Modern sepsis management emphasizes early recognition through clinical scoring systems and biomarkers, personalized resuscitation strategies, antimicrobial stewardship, and organ support optimization. Emerging therapies including immunomodulation and precision medicine approaches show promise for improving outcomes.

Keywords: sepsis, septic shock, qSOFA, lactate, antimicrobial stewardship, fluid resuscitation, vasopressors

---

Introduction

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, continues to challenge critical care practitioners worldwide. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) revolutionized our diagnostic approach, yet mortality remains substantial at 25-30% for sepsis and 40-50% for septic shock.¹ This review synthesizes current evidence and provides practical guidance for the contemporary management of sepsis in 2025.

Pathophysiology: Beyond the Inflammatory Cascade

The traditional view of sepsis as purely hyperinflammatory has evolved to recognize a complex interplay of pro- and anti-inflammatory responses, immune paralysis, and mitochondrial dysfunction.² Understanding this pathophysiologic complexity has informed targeted therapeutic approaches and personalized medicine strategies.

Key Pathophysiologic Concepts:

• Immune dysregulation: Early hyperinflammation followed by immunosuppression
• Endothelial dysfunction: Increased vascular permeability and coagulopathy
• Mitochondrial dysfunction: Impaired cellular respiration and energy production
• Complement activation: Alternative pathway dysregulation in severe cases

Recognition and Risk Stratification

Clinical Scoring Systems

Quick Sequential Organ Failure Assessment (qSOFA) remains the bedside screening tool of choice, with scores ≥2 indicating high risk for poor outcomes:

• Altered mental status (GCS <15)
• Systolic blood pressure ≤100 mmHg
• Respiratory rate ≥22/min

🔍 Clinical Pearl: qSOFA performs better outside the ICU for screening. In ICU patients, full SOFA scores provide superior prognostic accuracy.

Biomarkers in 2025

Lactate continues as the primary metabolic marker, with levels >2 mmol/L indicating tissue hypoperfusion. However, lactate clearance (>10% within 2-6 hours) may be more predictive than absolute values.³

Procalcitonin (PCT) remains valuable for:

• Distinguishing bacterial from viral infections
• Guiding antibiotic duration (target <0.5 ng/mL or 80% reduction)
• Monitoring treatment response

Emerging Biomarkers:

• Mid-regional pro-adrenomedullin (MR-proADM): Superior prognostic accuracy
• Presepsin: Rapid bacterial infection identification
• Neutrophil-to-lymphocyte ratio: Cost-effective prognostic marker

⚠️ Clinical Oyster: Normal procalcitonin doesn't exclude sepsis in immunocompromised patients, those with localized infections, or very early presentations.

The Hour-1 Bundle: Evolution of Early Management

The Surviving Sepsis Campaign's Hour-1 Bundle emphasizes immediate intervention:⁴

1. Measure lactate level
2. Obtain blood cultures before antibiotics
3. Administer broad-spectrum antibiotics
4. Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
5. Apply vasopressors if hypotensive during or after fluid resuscitation

🎯 Management Hack: The "SEPSIS" Mnemonic

• Screen with qSOFA
• Early blood cultures
• Procalcitonin and lactate
• Start antibiotics within 1 hour
• IV fluids 30 mL/kg if indicated
• Support circulation with vasopressors

Antimicrobial Therapy: Precision and Stewardship

Empirical Antibiotic Selection

First-line empirical therapy should consider:

• Local epidemiology and resistance patterns
• Patient risk factors (immunosuppression, recent healthcare exposure)
• Suspected source of infection
• Severity of presentation

Recommended empirical regimens:

• Community-acquired: Piperacillin-tazobactam or ceftriaxone + metronidazole
• Healthcare-associated: Anti-pseudomonal β-lactam + vancomycin
• Immunocompromised: Broad-spectrum coverage including anti-fungal consideration

Antibiotic Optimization Strategies

🔍 Clinical Pearl: The "4 R's" of antibiotic optimization:

1. Right drug: Based on likely pathogens and local resistance
2. Right dose: Consider pathophysiologic changes affecting pharmacokinetics
3. Right duration: Minimize based on clinical response and biomarkers
4. Right route: IV to oral conversion when appropriate

Pharmacokinetic Considerations:

• Increased volume of distribution requires higher loading doses
• Enhanced renal clearance in hyperdynamic patients may necessitate increased maintenance dosing
• Therapeutic drug monitoring for vancomycin, aminoglycosides, and β-lactams

Duration Guidance:

• Uncomplicated sepsis: 5-7 days if source controlled
• Use procalcitonin to guide discontinuation (target <0.5 ng/mL)
• Longer courses only if persistent infection focus or immunocompromise

Fluid Resuscitation: Beyond the 30 mL/kg Rule

Initial Resuscitation

The traditional approach of 30 mL/kg crystalloid within 3 hours has been refined based on recent evidence. The CLOVERS trial demonstrated no mortality benefit from restrictive versus liberal fluid strategies when protocolized.⁵

🎯 Management Hack: Use the "FLUID" approach:

• Fluid responsiveness assessment before additional boluses
• Lactate and perfusion monitoring
• Ultrasound-guided evaluation (IVC, cardiac function)
• Intravenous access optimization
• Dynamic assessment tools (passive leg raise, stroke volume variation)

Fluid Responsiveness Assessment

Static Parameters (Less Reliable):

• Central venous pressure (target abandoned)
• Pulmonary artery occlusion pressure

Dynamic Parameters (Preferred):

• Passive leg raise test (increase in stroke volume >15%)
• Stroke volume variation >13% (mechanically ventilated patients)
• Inferior vena cava collapsibility >50%

⚠️ Clinical Oyster: Fluid responsiveness doesn't equal fluid requirement. Even fluid-responsive patients may benefit from vasopressor initiation to avoid fluid overload.

Crystalloid vs. Colloid Debate

Recent meta-analyses confirm crystalloids as first-line therapy. Balanced crystalloids (lactated Ringer's, Plasma-Lyte) may reduce mortality compared to normal saline, particularly in patients receiving >2L fluid.⁶

Albumin may be considered in:

• Severe hypoalbuminemia (<2.5 g/dL)
• Refractory shock despite adequate crystalloid resuscitation
• Concurrent acute kidney injury

Vasopressor and Inotropic Support

First-Line Vasopressor Therapy

Norepinephrine remains the first-line vasopressor with superior outcomes compared to dopamine.⁷ Target mean arterial pressure (MAP) of 65 mmHg is appropriate for most patients, though individualization based on baseline blood pressure and comorbidities is essential.

🔍 Clinical Pearl: Higher MAP targets (75-85 mmHg) may benefit patients with:

• Chronic hypertension
• Cerebrovascular disease
• Chronic kidney disease

Second-Line Agents

Vasopressin (0.03 units/min) should be added when norepinephrine doses exceed 0.25-0.5 mcg/kg/min. Benefits include:

• Norepinephrine-sparing effect
• Improved renal function in some patients
• Reduced risk of arrhythmias

Epinephrine is reserved for refractory shock or patients with concurrent cardiac dysfunction.

🎯 Management Hack: The "MAPS" approach to vasopressor selection:

• MAP target individualized (usually 65 mmHg)
• Assess cardiac function (echocardiography)
• Perfusion markers (lactate, urine output, mental status)
• Side effect profile consideration

Inotropic Support

Dobutamine should be considered in patients with:

• Evidence of cardiac dysfunction (low cardiac output, high filling pressures)
• Persistent hypoperfusion despite adequate MAP
• Mixed cardiogenic-distributive shock

Adjunctive Therapies

Corticosteroids

Hydrocortisone (200 mg/day) is recommended for patients with refractory septic shock requiring high-dose vasopressors despite adequate fluid resuscitation.⁸ The ADRENAL and APROCCHSS trials support mortality benefits in severe shock.

Indications:

• Vasopressor-dependent shock >4-6 hours
• Norepinephrine equivalent >0.25 mcg/kg/min
• Consider relative adrenal insufficiency testing

Blood Product Management

Restrictive transfusion strategy (hemoglobin <7 g/dL) is appropriate for most septic patients without active bleeding or coronary artery disease.⁹

Platelet transfusion thresholds:

• <10,000/μL for bleeding risk reduction
• <50,000/μL for active bleeding or procedures

Fresh frozen plasma only for documented coagulopathy with bleeding or planned procedures.

Renal Replacement Therapy

Continuous renal replacement therapy (CRRT) is preferred over intermittent hemodialysis in hemodynamically unstable patients. Initiation timing remains controversial, but early initiation may benefit patients with severe fluid overload or severe acidosis.

🔍 Clinical Pearl: The "KDIGO" criteria for RRT initiation in sepsis:

• Severe acidosis (pH <7.15)
• Severe hyperkalemia (>6.5 mEq/L)
• Severe fluid overload with pulmonary edema
• Uremic complications

Emerging Therapies and Future Directions

Immunomodulation

Tocilizumab (IL-6 receptor antagonist) shows promise in COVID-19-associated sepsis but remains investigational for bacterial sepsis.

Anakinra (IL-1 receptor antagonist) demonstrated mortality benefits in patients with hyperinflammation and hepatobiliary dysfunction.¹⁰

Precision Medicine Approaches

Endotyping based on immune status, biomarker profiles, and genetic markers may guide personalized therapy:

• Inflammopathic endotype: May benefit from immunosuppression
• Immunoparalysis endotype: May require immune stimulation

Metabolic Interventions

Thiamine supplementation (200 mg every 12 hours) is recommended for patients with suspected deficiency or refractory shock.

Vitamin C, hydrocortisone, and thiamine (HAT therapy) remains controversial with mixed trial results.

Quality Improvement and Bundle Compliance

Key Performance Indicators

Process Measures:

• Time to antibiotic administration (<1 hour)
• Appropriate empirical antibiotic selection
• Adequate initial fluid resuscitation
• Source control timing

Outcome Measures:

• Hospital mortality
• Length of stay
• Antibiotic duration
• Healthcare-associated infections

🎯 Management Hack: Implement sepsis "huddles" during shift changes to:

• Review sepsis patients systematically
• Assess bundle compliance
• Plan de-escalation strategies
• Coordinate multidisciplinary care

Special Populations

Immunocompromised Patients

Broader empirical coverage including:

• Anti-fungal therapy consideration
• Pneumocystis prophylaxis if indicated
• Viral pathogen evaluation
• Lower threshold for invasive diagnostic procedures

Elderly Patients

Modified approach considerations:

• More conservative fluid resuscitation
• Lower MAP targets may be appropriate
• Increased risk of adverse drug reactions
• Earlier consideration of goals of care discussions

Pregnancy

Physiologic changes affecting management:

• Increased cardiac output and blood volume
• Lower baseline blood pressure
• Increased minute ventilation
• Modified antibiotic choices (avoid quinolones, tetracyclines)

Practical Clinical Pearls and Oysters

🔍 Clinical Pearls:

1. Early lactate clearance (>10% in 2 hours) is more predictive than absolute values
2. Fever >38.3°C in the first 24 hours after antibiotic initiation often represents cytokine release, not treatment failure
3. Procalcitonin doubling time <24 hours suggests treatment failure or resistant pathogens
4. Urine output <0.5 mL/kg/hr for >2 hours is an early indicator of organ dysfunction
5. Mental status changes may be the earliest sign of sepsis in elderly patients

⚠️ Clinical Oysters:

1. Normal white blood cell count doesn't exclude sepsis, especially in immunocompromised patients
2. Hypothermia (<36°C) carries worse prognosis than fever in sepsis
3. Positive blood cultures occur in only 30-50% of sepsis cases
4. qSOFA score of 0-1 doesn't rule out sepsis in high-risk populations
5. Fluid overload after initial resuscitation is associated with increased mortality

🎯 Management Hacks Summary:

The "SEPSIS SAVES" Protocol:

• Screen high-risk patients systematically

• Early recognition and risk stratification

• Prompt antibiotic administration (<1 hour)

• Source control evaluation and intervention

• Initial resuscitation with 30 mL/kg if indicated

• Support circulation with appropriate vasopressors

• Stewardship-guided antibiotic optimization

• Adjunctive therapies when indicated

• Vital organ support (renal, respiratory)

• Endotype-directed precision therapy

• Systematic quality improvement

Conclusion

Sepsis management in 2025 emphasizes rapid recognition, early intervention, and personalized care approaches. The integration of traditional clinical assessments with novel biomarkers, advanced monitoring techniques, and emerging therapies offers unprecedented opportunities to improve patient outcomes. Success requires systematic implementation of evidence-based bundles, commitment to antimicrobial stewardship, and continuous quality improvement efforts.

Critical care practitioners must remain vigilant for sepsis recognition while avoiding overdiagnosis and overtreatment. The future of sepsis care lies in precision medicine approaches that match therapeutic interventions to individual patient endotypes and disease trajectories.

References

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.

2. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17(7):407-420.

3. Bakker J, Postelnicu R, Mukherjee V. Lactate: where are we now? Crit Care Med. 2021;49(8):1305-1316.

4. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;44(6):925-928.

5. Shapiro NI, Douglas IS, Brower RG, et al. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med. 2023;388(6):499-510.

6. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839.

7. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887.

8. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809-818.

9. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371(15):1381-1391.

10. Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med. 2021;27(10):1752-1760.

---

Conflicts of Interest: The authors declare no conflicts of interest.

Funding: No specific funding was received for this review.

Data Availability: This review article does not contain original research data.